Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF

JJL Jacobs, B Scheijen, JW Voncken… - Genes & …, 1999 - genesdev.cshlp.org
JJL Jacobs, B Scheijen, JW Voncken, K Kieboom, A Berns, M van Lohuizen
Genes & development, 1999genesdev.cshlp.org
The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the
basis for this collaboration was not understood. We recently identified the ink4a–ARF tumor
suppressor locus as a critical downstream target of the Polycomb-group transcriptional
repressor Bmi-1. Others have shown that part of Myc's ability to induce apoptosis depends
on induction of p19arf. Here we demonstrate that down-regulation of ink4a–ARF by Bmi-1
underlies its ability to cooperate with Myc in tumorigenesis. Heterozygosity for bmi-1 inhibits …
The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the basis for this collaboration was not understood. We recently identified the ink4a–ARF tumor suppressor locus as a critical downstream target of the Polycomb-group transcriptional repressor Bmi-1. Others have shown that part of Myc's ability to induce apoptosis depends on induction of p19arf. Here we demonstrate that down-regulation of ink4a–ARF by Bmi-1 underlies its ability to cooperate with Myc in tumorigenesis. Heterozygosity for bmi-1 inhibits lymphomagenesis in Eμ–myc mice by enhancing c-Myc-induced apoptosis. We observe increased apoptosis in bmi-1−/− lymphoid organs, which can be rescued by deletion of ink4a–ARF or overexpression of bcl2. Furthermore, Bmi-1 collaborates with Myc in enhancing proliferation and transformation of primary embryo fibroblasts (MEFs) in an ink4a–ARF dependent manner, by prohibiting Myc-mediated induction of p19arf and apoptosis. We observe strong collaboration between the Eμ–myc transgene and heterozygosity for ink4a–ARF, which is accompanied by loss of the wild-type ink4a–ARF allele and formation of highly aggressive B-cell lymphomas. Together, these results reinforce the critical role of Bmi-1 as a dose-dependent regulator of ink4a–ARF, which on its turn acts to prevent tumorigenesis on activation of oncogenes such as c-myc.
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